Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark.
Dermatology. 2011;222(4):292-6. doi: 10.1159/000328404. Epub 2011 Jul 1.
Darier disease is an autosomal dominant genodermatosis caused by germline mutations in the ATP2A2 gene. Clinical expression is variable, including rare segmental phenotypes thought to be caused by postzygotic mosaicism. Genetic counseling of segmental Darier patients is complex, as risk of transmitting a nonsegmental phenotype to offspring is of unknown magnitude. We present the first in-depth molecular analysis of a mosaic patient with segmental disease, quantifying proportions of mutated and normal alleles in various tissues. Pyrosequence analysis of DNA from semen, affected and normal skin, peripheral leukocytes and hair revealed an uneven distribution of the mutated allele, from 14% in semen to 37% in affected skin. We suggest a model for segmental manifestation expression where a threshold number of mutated cells is needed for manifestation development. We further recommend molecular analysis of the ATP2A2 gene in semen of male patients with segmental Darier disease to improve genetic counseling.
大疱性先天性鱼鳞病样红皮病（Darier disease）是一种常染色体显性遗传皮肤病，由 ATP2A2 基因突变引起。临床表型具有异质性，包括罕见的节段型表型，被认为是合子后嵌合体导致的。节段型 Darier 病患者的遗传咨询较为复杂，因为向后代传递非节段型表型的风险程度尚不清楚。我们首次对节段型疾病的嵌合体患者进行了深入的分子分析，定量分析了不同组织中突变和正常等位基因的比例。对精液、皮损、外周血白细胞和头发中的 DNA 进行焦磷酸测序分析，发现突变等位基因的分布不均匀，从精液中的 14%到皮损中的 37%不等。我们提出了节段性疾病表现的表达模型，即需要一定数量的突变细胞才能表现出疾病。因此，我们建议对节段型 Darier 病男性患者的精液进行 ATP2A2 基因突变的分子分析，以改善遗传咨询。
